title: CD40 ligand/CD40 stimulation regulates the production of IFN-gamma from human peripheral blood mononuclear cells in an IL-12- and/or CD28-dependent manner.
abstract: CD40 ligand (CD40L)/CD40 costimulation is an important regulator of Th1 responses. Two mechanisms by which CD40L/CD40 stimulation may enhance IFN-gamma are via direct induction of IL-12 and augmentation of the expression of costimulatory molecules such as B7 from APCs. We examined the ability of CD40L/CD40 stimulation to regulate the production of IFN-gamma through IL-12 and/or CD28 costimulation from human PBMCs stimulated with T cell-specific stimuli. The roles of exogenous and endogenous CD40L/CD40 stimulation were evaluated using a trimeric soluble CD40L agonist (CD40T) and an anti-CD40L Ab, respectively. The presence of CD40T in cultures increased the production of IL-12 and IFN-gamma from PBMCs stimulated with varying amounts of PHA. The mechanism, however, by which CD40T enhanced IFN-gamma varied according to the level of T cell activation. Under maximal stimulatory conditions (PHA, 1/100), an IL-12-dependent pathway was dominant. At relatively low levels of T cell stimulation (PHA, 1/500 and 1/1000), however, an additional IL-12-independent CD28-dependent pathway was elucidated. We further studied the role of exogenous CD28 stimulation in regulating the production of IFN-gamma. The enhancement of IFN-gamma production induced by direct CD28 stimulation was primarily dependent on endogenous IL-12 or CD40L/CD40 stimulation. Together, these data suggest that the production of IFN-gamma involves a complex interaction between two interdependent, yet distinct, costimulatory pathways and provide evidence that CD40T may be an effective adjuvant for the enhancement of responses.
authors.affiliation: Lymphokine Regulation Unit, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: McDyer
authors.forename: T J
authors.initials: TJ
authors.lastname: Goletz
authors.forename: E
authors.initials: E
authors.lastname: Thomas
authors.forename: C H
authors.initials: CH
authors.lastname: June
authors.forename: R A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology*; D019013:CD40 Antigens / Q000494:pharmacology / Q000502:physiology*; D023201:CD40 Ligand; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000187:drug effects; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D010835:Phytohemagglutinins / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D010835:Phytohemagglutinins; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma